The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity

Mahdia Benkhoucha,Patrice H Lalive,Paul R Walker,Gregory Schneiter,Nicolas Molnarfi

doi:10.1186/1742-2094-10-154

Mahdia Benkhoucha, Patrice H Lalive + Show 3 more

Open Access

https://doi.org/10.1186/1742-2094-10-154

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Abstract

BackgroundAccumulating evidence suggests a deleterious role for CD8+ T cells in multiple sclerosis (MS) pathogenesis. We have recently reported that hepatocyte growth factor (HGF), a potent neuroprotective factor, limits CD4+ T cell-mediated autoimmune neuroinflammation by promoting tolerogenic dendritic cells (DCs) and subsequently regulatory T cells. Whether HGF modulates cell-mediated immunity driven by MHC class I-restricted CD8+ T cells remains to be determined.MethodsHere we examined whether HGF regulates antigen-specific CD8+ T cell responses using an established model of murine cytotoxic T lymphocyte (CTL)-mediated killing.ResultsWe found that HGF treatment of gp100-pulsed DCs reduced the activation of gp100-specific T cell receptor (Pmel-1) CD8+ T cells and subsequent MHC class I-restricted CTL-mediated cytolysis of gp100-pulsed target cells. The levels of perforin, granzyme B, IFN-γ, and the degranulation marker CD107a as well as Fas ligand were decreased among CD8+ T cells, suggestive of a dual inhibitory effect of HGF on the perforin/granzyme B- and Fas-based lytic pathways in cell-mediated cytotoxicity. Treatment of CD8+ T cells with concanamycin A, a potent inhibitor of the perforin-mediated cytotoxic pathway, abrogated CTL cytotoxicity indicating that blockade of the perforin-dependent killing is a major mechanism by which HGF diminished cytolysis of gp100-pulsed target cells. Moreover, HGF suppressed the generation of effector memory CTLs.ConclusionsOur findings indicate that HGF treatment limits both the generation and activity of effector CTL from naïve CD8+ T cells. Complementary to its impact on CD4+ T-cell CNS autoimmunity and myelin repair, our findings further suggest that HGF treatment could be exploited to control CD8+ T-cell-mediated, MHC I-restricted autoimmune dysfunctions such as MS.

Highlights

Accumulating evidence suggests a deleterious role for CD8+ T cells in multiple sclerosis (MS) pathogenesis
hepatocyte growth factor (HGF) limits effector Ag-specific cytotoxic T lymphocyte (CTL) generation In order to assess the capacity of HGF to modulate the generation of antigen-specific CD8+ T cells, Pmel-1 T cell receptor (TCR) transgenic splenocytes were stimulated with gp10025-33 for 1 h, and cultured with IL-2 alone or in combination with HGF for 5 days
(c) Flow cytometry analysis of effector cells showed that HGF increased the amount on a per cell basis of cytotoxic T-lymphocyte antigen 4 (CTLA4) starting at day 3 but not CD28 molecules, as indicated by comparative geometric mean of fluorescence (GMEAN) ± SEM of three independent experiments

Summary

Introduction

Accumulating evidence suggests a deleterious role for CD8+ T cells in multiple sclerosis (MS) pathogenesis. Histopathological and neurobiological studies in MS suggest that CD8+ T cells hold an active role in disease pathogenesis by targeting oligodendrocytes and the myelin sheath [11]. Due to their ability to function as professional antigenpresenting cells (APCs), CD11c+ myeloid DCs play an undisputed role in inciting autoimmunity. In EAE, DCs are critical APCs for the induction of both myelin-specific CD4+ and CD8+ T cells, and are a prominent component of CNS-infiltrating cells [12,13]. Current efforts for the treatment of autoimmune pathogeneses requiring tolerance recovery are focused in the identification of molecules that control the development of tolerogenic DCs [15]

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